Methamphetamine blunts Ca2+ currents and excitatory synaptic transmission through D1/5 receptor-mediated mechanisms in the mouse medial prefrontal cortex

JAVIER A. MUÑIZ; FRANCISCO URBANO; BETINA GONZALEZ; JEAN LUD CADET; VERONICA BISAGNO; CELESTE RIVERO-ECHETO; EDGAR GARCIA-RILL

ADDICTION BIOLOGY

WILEY-BLACKWELL PUBLISHING, INC

Lugar: Londres; Año: 2016

1355-6215

Psychostimulant addiction is associated with dysfunctions in frontal cortex. Previous data demonstrated that repeated exposure to methamphetamine (METH) can alter prefrontal cortex (PFC) dependent functions. Here, we show that withdrawal from repetitive non-contingent METH administration (7 days, 1mg/kg) depressed voltage-dependent calcium currents (ICa) and increased IH amplitude and the paired-pulse ratio of evoked EPSCs in deep-layer pyramidal mPFC neurons. Most of these effects were blocked by systemic co-administration of the D1/D5 receptor antagonist SCH23390 (0.5 and 0.05 mg/kg). In vitro METH (i.e bath-applied to slices from naïve-treated animals) was able to emulate its systemic effects on ICa and evoked EPSCs paired-pulse ratio. We also provide evidence of altered mRNA expression of i) voltage-gated calcium channels P/Q-type Cacna1a (Cav2.1), N-type Cacna1b (Cav2.2), T-type Cav3.1 Cacna1g, Cav3.2 Cacna1h, Cav3.3 Cacna1i and the auxiliary subunit Cacna2d1 (a2d1), ii) hyperpolarization-activated cyclic nucleotide-gated channels Hcn1 and Hcn2 and iii) glutamate receptors subunits AMPA-type Gria1, NMDA-type Grin1 and metabotropic Grm1 in the mouse mPFC after repeated METH treatment. Moreover, we show that some of these changes in mRNA expression were sensitive D1/5 receptor blockade.Altogether these altered mechanisms affecting synaptic physiology and transcriptional regulation may underlie prefrontal cortex functional alterations that could lead to PFC impairments observed in METH-addicted individuals.